Investigation of Ketogenic Diet Metabolites as a Therapeutic for Alzheimer’s Disease in a Drosophila Model of Glial Tauopathy

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Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder that is characterized by progressive neuronal and synaptic degeneration, as well as decreased cognition over time. AD is prevalent in today’s society, comprising 60-80% of dementia cases, and therefore it is an essential disease to study. Although extensive research has been done, the cause and progression of the disease is still unknown. However, one of the hallmarks of AD is intracellular neurofibrillary tangles (NFTs), which are composed of the protein tau. High tau concentrations have been shown to correlate with fast cognitive decline; therefore, it is
hypothesized that lowering overall tau levels in the brain will reduce AD symptoms. Moreover, there is evidence that AD patients have a reduced glycolytic metabolism, so it is predicted that administration of a ketogenic diet – which produces ketone bodies that bypass glycolysis to enter mitochondrial metabolism directly- will ameliorate tau toxicity. This hypothesis was tested by
feeding the ketone body β-hydroxybutyrate (βHB) to Drosophila overexpressing human wild-type tau in their glia, and quantifying the level of tau in their brains with Western blot. Furthermore, since ketone bodies have been shown to modulate ATP-sensitive potassium (KATP) channel activity, the role of KATP channels was investigated by administering the allosteric KATP inhibitor tolbutamide. Our results found that: 1) Administration of βHB lowers overall tau in the brain as long as the flies are raised on the diet 2) Reduction in relative tau levels is more pronounced after four weeks on βHB 3) Tolbutamide indirectly
increases the amount of tau in the brain and reverses the effects of the ketogenic diet, indicating that KATP channels may have a mechanistic role in regulating tau expression and neuroexcitability.